POTIGA can cause retinal abnormalities with
funduscopic features similar to those seen in retinal pigment dystrophies,
which are known to result in damage to the photoreceptors and vision loss.

Some patients with retinal abnormalities have been
found to have abnormal visual acuity. It is not possible to determine whether
POTIGA caused this decreased visual acuity, as baseline assessments are not
available for these patients.

Approximately one third of the patients who had eye
examinations performed after approximately 4 years of treatment were found to
have retinal pigmentary abnormalities. An earlier onset cannot be ruled out,
and it is possible that retinal abnormalities were present earlier in the
course of exposure to POTIGA. The rate of progression of retinal abnormalities
and their reversibility are unknown.

POTIGA should only be used in patients who have
responded inadequately to several alternative treatments and for whom the
benefits outweigh the potential risk of vision loss. Patients who fail to show
substantial clinical benefit after adequate titration should be discontinued
from POTIGA.

If retinal pigmentary abnormalities or vision changes
are detected, POTIGA should be discontinued unless no other suitable treatment
options are available and the benefits of treatment outweigh the potential risk
of vision loss.

DESCRIPTION

The chemical name of ezogabine is
N-[2-amino-4-(4-fluorobenzylamino)-phenyl] carbamic acid ethyl ester, and it
has the following structure:

The empirical formula is C16H18FN3O2,
representing a molecular weight of 303.3. Ezogabine is a white to slightly
colored, odorless, tasteless, crystalline powder. At room temperature,
ezogabine is practically insoluble in aqueous media at pH values above 4, while
the solubility is higher in polar organic solvents. At gastric pH, ezogabine is
sparingly soluble in water (about 16 g/L). The pKa is approximately 3.7
(basic).

For Consumers

What are the possible side effects of ezogabine (Potiga)?

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

Report any new or worsening symptoms to your doctor, such as: mood or behavior changes, depression, anxiety, panic attacks, or if you feel agitated, hostile, aggressive, restless, hyperactive (mentally or physically), or have thoughts about suicide or hurting yourself.

INDICATIONS

POTIGA® is indicated as adjunctive treatment of
partial-onset seizures in patients aged 18 years and older who have responded inadequately to
several alternative treatments and for whom the benefits outweigh the risk of
retinal abnormalities and potential decline in visual acuity [see WARNINGS
AND PRECAUTIONS].

DOSAGE AND ADMINISTRATION

Dosing Information

The initial dosage should be 100 mg 3 times daily (300 mg
per day). The dosage should be increased gradually at weekly intervals by no
more than 50 mg 3 times daily (increase in the daily dose of no more than 150
mg per day) up to a maintenance dosage of 200 mg to 400 mg 3 times daily (600
mg to 1,200 mg per day), based on individual patient response and tolerability.
This information is summarized in Table 1 under Dosing in Specific Populations.
In the controlled clinical trials, 400 mg 3 times daily showed limited evidence
of additional improvement in seizure reduction, but an increase in adverse
events and discontinuations, compared to the 300 mg 3 times daily dosage. The
safety and efficacy of doses greater than 400 mg 3 times daily (1,200 mg per
day) have not been examined in controlled trials.

POTIGA should be given orally in 3 equally divided doses
daily, with or without food.

POTIGA Tablets should be swallowed whole.

If POTIGA is discontinued, the dosage should be gradually
reduced over a period of at least 3 weeks, unless safety concerns require
abrupt withdrawal.

Dosing Considerations to Mitigate the Risk of Visual
Adverse Reactions

Because POTIGA may cause retinal abnormalities with
long-term use, patients who fail to show substantial clinical benefit after
adequate titration should be discontinued from POTIGA. Testing of visual
function should be done at baseline and every 6 months during therapy with
POTIGA. Patients who cannot be monitored should usually not be treated with POTIGA.
If retinal pigmentary abnormalities or vision changes are detected, POTIGA
should be discontinued unless no other suitable treatment options are available
and the benefits of treatment outweigh the potential risk of vision loss [see WARNINGS
AND PRECAUTIONS].

Dosing in Specific Populations

No adjustment in dosage is required for patients with
mild renal or hepatic impairment (see Table 1). Dosage adjustment is required
in geriatric and patients with moderate and greater renal or hepatic impairment
(see Table 1).

Table 1: Dosing in Specific Populations

Specific Population

Initial Dose

Titration

Maximum Dose

General Dosing

General population (including patients with mild renal or hepatic impairment)

Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions and for varying durations, adverse reaction frequencies
observed in the clinical trials of a drug cannot be directly compared with
frequencies in the clinical trials of another drug and may not reflect the frequencies
observed in practice.

POTIGA was administered as adjunctive therapy to 1,365
patients with epilepsy in all controlled and uncontrolled clinical studies
during the premarketing development. A total of 801 patients were treated for
at least 6 months, 585 patients were treated for 1 year or longer, and 311 patients
were treated for at least 2 years.

Adverse Reactions Leading to Discontinuation in All
Controlled Clinical Studies

In the 3 randomized, double-blind, placebo-controlled
studies, 199 of 813 patients (25%) receiving POTIGA and 45 of 427 patients
(11%) receiving placebo discontinued treatment because of adverse reactions.
The most common adverse reactions leading to withdrawal in patients receiving
POTIGA were dizziness (6%), confusional state (4%), fatigue (3%), and somnolence
(3%).

Table 4: Adverse Reaction Incidence in
Placebo-Controlled Adjunctive Trials in Adult Patients With Partial Onset
Seizures (Adverse reactions in at least 2% of patients treated with POTIGA in
any treatment group and numerically more frequent than in the placebo group.)

Comparison of Gender, Age, and Race

The overall adverse reaction profile of POTIGA was
similar for females and males.

There are insufficient data to support meaningful
analyses of adverse reactions by age or race. Approximately 86% of the
population studied was Caucasian, and 0.8% of the population was older than 65
years.

DRUG INTERACTIONS

Antiepileptic Drugs

The potentially significant interactions between POTIGA
and concomitant AEDs are summarized in Table 5.

a Based on results of a Phase 2 study.b Inducer for uridine 5'-diphosphate (UDP)-glucuronyltransferases
(UGTs).c A decrease in dosage of POTIGA should be considered when
carbamazepine or phenytoin is discontinued.[See CLINICAL PHARMACOLOGY]

Digoxin

Data from an in vitro study showed that the N-acetyl
metabolite of ezogabine (NAMR) inhibited P-glycoprotein-mediated transport of
digoxin in a concentration-dependent manner, indicating that NAMR may inhibit
renal clearance of digoxin. Administration of POTIGA at therapeutic doses may
increase digoxin serum concentrations. Serum levels of digoxin should be monitored
[see CLINICAL PHARMACOLOGY].

Alcohol

Alcohol increased systemic exposure to POTIGA. Patients
should be advised of possible worsening of ezogabine's general dose-related
adverse reactions if they take POTIGA with alcohol [see CLINICAL
PHARMACOLOGY].

Laboratory Tests

Ezogabine has been shown to interfere with clinical
laboratory assays of both serum and urine bilirubin, which can result in
falsely elevated readings.

Drug Abuse And Dependence

Controlled Substance

POTIGA is a Schedule V controlled substance.

Abuse

A human abuse potential study was conducted in
recreational sedative-hypnotic abusers (n = 36) in which single oral doses of
ezogabine (300 mg [n = 33], 600 mg [n = 34], 900 mg [n = 6]), the
sedative-hypnotic alprazolam (1.5 mg and 3.0 mg), and placebo were
administered. Euphoria-type subjective responses to the 300-mg and 600-mg doses
of ezogabine were statistically different from placebo but statistically
indistinguishable from those produced by either dose of alprazolam. Adverse
events reported following administration of single oral doses of 300 mg, 600
mg, and 900 mg ezogabine given without titration included euphoric mood (18%, 21%,
and 33%, respectively; 8% from placebo), hallucination (0%, 0%, and 17%,
respectively; 0% from placebo) and somnolence (18%, 15%, and 67%, respectively;
15% from placebo).

In the 3 randomized, double-blind, placebo-controlled
Phase 2 and 3 clinical studies, patients with partial seizures who received
oral ezogabine (300 mg to 1,200 mg) reported euphoric mood (0.5%) and feeling
drunk (0.9%), while those who received placebo did not report either adverse
event (0%).

Dependence

In a 28-day physical dependence study in which rats
received daily ezogabine administration, abrupt drug discontinuation produced
behavioral changes that included piloerection, increases in high step gait, and
tremors, compared to vehicle-treated animals. These data show that ezogabine
produces a withdrawal syndrome indicative of physical dependence.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Retinal Abnormalities and Potential Vision Loss

POTIGA can cause abnormalities of the retina. The
abnormalities seen in patients treated with POTIGA have funduscopic features
similar to those seen in retinal pigment dystrophies that are known to result
in damage to photoreceptors and vision loss.

The retinal abnormalities observed with POTIGA have been
reported in patients who were originally enrolled in clinical trials with
POTIGA and who have generally taken the drug for a long period of time in 2
ongoing extension studies. Approximately one third of the patients who had eye
examinations performed after approximately 4 years of treatment were found to have
retinal pigmentary abnormalities. However, an earlier onset cannot be ruled
out, and it is possible that retinal abnormalities were present earlier in the
course of exposure to POTIGA. POTIGA causes skin, scleral, nail, and mucous
membrane discoloration and it is not clear whether this discoloration is
related to retinal abnormalities. Approximately
15% of patients with retinal pigmentary abnormalities had no such discoloration.

Funduscopic abnormalities have most commonly been
described as perivascular pigmentation (bone spicule pattern) in the retinal
periphery and/or as areas of focalretinal pigment epithelium clumping. Although
some of the patients with retinal abnormalities have been found to have
abnormal visual acuity, it is not possible to assess whether POTIGA caused their
decreased visual acuity, as baseline assessments are not available for these
patients. Two patients with retinal abnormalities have had more extensive
diagnostic retinal evaluations. The results of these evaluations were
consistent with a retinal dystrophy, including abnormalities in the
electroretinogram and electrooculogram of both patients, with abnormal
fluorescein angiography and diminished sensitivity on visual field testing in
one patient.

The rate of progression of retinal abnormalities and the
reversibility after drug discontinuation are unknown.

Because of the observed ophthalmologic adverse reactions,
POTIGA should only be used in patients who have responded inadequately to
several alternative treatments and for whom the benefits outweigh the risk of
retinal abnormalities and potential vision loss. Patients who fail to show
substantial clinical benefit after adequate titration should be discontinued
from POTIGA.

Patients should have baseline ophthalmologic testing by
an ophthalmic professional and follow-up testing every 6 months. The best
method of detection of these abnormalities and the optimal frequency of
periodic ophthalmologic monitoring are unknown. Patients who cannot be monitored
should usually not be treated with POTIGA. The ophthalmologic monitoring
program should include visual acuity testing and dilated fundus photography.
Additional testing may include fluorescein angiograms (FA), ocular coherence
tomography (OCT), perimetry, and electroretinograms (ERG). If retinal
pigmentary abnormalities or vision changes are detected, POTIGA should be
discontinued unless no other suitable treatment options are available and the benefits
of treatment outweigh the potential risk of vision loss.

Urinary Retention

POTIGA caused urinary retention in clinical trials.
Urinary retention was generally reported within the first 6 months of
treatment, but was also observed later. Urinary retention was reported as an
adverse event in 29 of 1,365 (approximately 2%) patients treated with POTIGA in
the open-label and placebo-controlled epilepsy database [see Clinical
Studies]. Of these 29 patients, 5 (17%) required catheterization, with
post-voiding residuals of up to 1,500 mL. POTIGA was discontinued in 4 patients
who required catheterization. Following discontinuation, these 4 patients were
able to void spontaneously; however, 1 of the 4 patients continued intermittent
self-catheterization. A fifth patient continued treatment with POTIGA and was
able to void spontaneously after catheter removal. Hydronephrosis occurred in 2
patients, one of whom had associated renal function impairment that resolved
upon discontinuation of POTIGA. Hydronephrosis was not reported in placebo
patients.

In the placebo-controlled epilepsy trials, “urinary
retention,” “urinary hesitation,” and “dysuria” were reported in 0.9%, 2.2%,
and 2.3% of patients on POTIGA, respectively, and in 0.5%, 0.9%, and 0.7% of
patients on placebo, respectively.

Because of the increased risk of urinary retention on
POTIGA, urologic symptoms should be carefully monitored. Closer monitoring is
recommended for patients who have other risk factors for urinary retention
(e.g., benign prostatic hyperplasia [BPH]), patients who are unable to
communicate clinical symptoms (e.g., cognitively impaired patients), or
patients who use concomitant medications that may affect voiding (e.g.,
anticholinergics). In these patients, a comprehensive evaluation of urologic
symptoms prior to and during treatment with POTIGA may be appropriate.

Skin Discoloration

POTIGA can cause skin discoloration. The skin
discoloration is generally described as blue, but has also been described as
grey-blue or brown. It is predominantly on or around the lips or in the nail
beds of the fingers or toes, but more widespread involvement of the face and
legs has also been reported. Discoloration of the palate, sclera, and
conjunctiva has also been reported.

Approximately 10% of patients in long-term clinical
trials developed skin discoloration, generally after 2 or more years of
treatment and at higher doses (900 mg or greater) of POTIGA. Among patients in
whom the status of both skin, nail, lip, or mucous membrane discoloration and
retinal pigmentary abnormalities are reported, approximately a quarter of those
with skin, nail, lip, or mucous membrane discoloration had concurrent retinal
pigmentary abnormalities.

Information on the consequences, reversibility, time to
onset, and pathophysiology of the skin abnormalities remains incomplete. The
possibility of more extensive systemic involvement has not been excluded. If a
patient develops skin discoloration, serious consideration should be given to
changing to an alternate medication.

Neuro-Psychiatric Symptoms

Confusional state, psychotic symptoms, and hallucinations
were reported more frequently as adverse reactions in patients treated with
POTIGA than in those treated with placebo in placebo-controlled epilepsy trials
(see Table 2). Discontinuations resulting from these reactions were more common
in the drug-treated group (see Table 2). These effects were dose-related and generally
appeared within the first 8 weeks of treatment. Half of the patients in the
controlled trials who discontinued POTIGA due to hallucinations or psychosis
required hospitalization.

Approximately two-thirds of patients with psychosis in
controlled trials had no prior psychiatric history. The psychiatric symptoms in
the vast majority of patients in both controlled and openlabel trials resolved
within 7 days of discontinuation of POTIGA. Rapid titration at greater than the
recommended doses appeared to increase the risk of psychosis and
hallucinations.

Dizziness and Somnolence

POTIGA causes dose-related increases in dizziness and
somnolence [see ADVERSE REACTIONS]. In placebo-controlled trials in
patients with epilepsy, dizziness was reported in 23% of patients treated with
POTIGA and 9% of patients treated with placebo. Somnolence was reported in 22%
of patients treated with POTIGA and 12% of patients treated with placebo. In these
trials 6% of patients on POTIGA and 1.2% on placebo discontinued treatment
because of dizziness; 3% of patients on POTIGA and < 1.0% on placebo
discontinued because of somnolence.

Most of these adverse reactions were mild to moderate in
intensity and occurred during the titration phase. For those patients continued
on POTIGA, dizziness and somnolence appeared to diminish with continued use.

QT Interval Effect

A study of cardiac conduction showed that POTIGA produced
a mean 7.7-msec QT prolongation in healthy volunteers titrated to 400 mg 3
times daily. The QT-prolonging effect occurred within 3 hours. The QT interval
should be monitored when POTIGA is prescribed with medicines known to increase
QT interval and in patients with known prolonged QT interval, congestive heart
failure, ventricularhypertrophy, hypokalemia, or hypomagnesemia [see CLINICAL
PHARMACOLOGY].

Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including POTIGA, increase
the risk of suicidal thoughts or behavior in patients taking these drugs for
any indication. Patients treated with any AED for any indication should be
monitored for the emergence or worsening of depression, suicidal thoughts or
behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials
(mono- and adjunctive-therapy) of 11 different AEDs showed that patients
randomized to one of the AEDs had approximately twice the risk (adjusted
relative risk 1.8, 95% confidence interval [CI]: 1.2, 2.7) of suicidal thinking
or behavior compared to patients randomized to placebo. In these trials, which
had a median treatment duration of 12 weeks, the estimated incidence of
suicidal behavior or ideation among 27,863 AED-treated patients was 0.43% compared
to 0.24% among 16,029 placebotreated patients, representing an increase of
approximately 1 case of suicidal thinking or behavior for every 530 patients
treated. There were 4 suicides in drug-treated patients in the trials and none
in placebo-treated patients, but the number is too small to allow any
conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with
AEDs was observed as early as 1 week after starting treatment with AEDs and
persisted for the duration of treatment assessed. Because most trials included
in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts
or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally
consistent among drugs in the data analyzed. The finding of increased risk with
AEDs of varying mechanism of action and across a range of indications suggests
that the risk applies to all AEDs used for any indication. The risk did not
vary substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 3 shows absolute and relative risk by indication
for all evaluated AEDs.

Table 3: Risk of Suicidal Thoughts or Behaviors by
Indication for Antiepileptic Drugs in the Pooled Analysis

The relative risk for suicidal thoughts or behavior was
higher in clinical trials in patients with epilepsy than in clinical trials in
patients with psychiatric or other conditions, but the absolute risk
differences were similar for epilepsy and psychiatric indications.

Anyone considering prescribing POTIGA or any other AED
must balance this risk with the risk of untreated illness. Epilepsy and many
other illnesses for which AEDs are prescribed are themselves associated with
morbidity and mortality and an increased risk of suicidal thoughts and
behavior. Should suicidal thoughts and behavior emerge during treatment, the
prescriber needs to consider whether the emergence of these symptoms in any
given patient may be related to the illness being treated.

Patients, their caregivers, and families should be
informed that AEDs increase the risk of suicidal thoughts and behavior and
should be advised of the need to be alert for the emergence or worsening of the
signs and symptoms of depression; any unusual changes in mood or behavior; or
the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.

Withdrawal Seizures

As with all AEDs, when POTIGA is discontinued, it should
be withdrawn gradually when possible to minimize the potential of increased
seizure frequency [see DOSAGE AND ADMINISTRATION]. The dosage of POTIGA
should be reduced over a period of at least 3 weeks, unless safety concerns
require abrupt withdrawal.

Patient Counseling Information

Retinal Abnormalities and Potential Vision Loss

Inform patients of the risk of retinal abnormalities and
possible risk of vision loss, which may be permanent [see WARNINGS AND
PRECAUTIONS]. All patients taking POTIGA should participate in baseline and
periodic ophthalmologic monitoring of vision by an ophthalmic professional.
Inform patients that if they suspect any vision changes, they should notify
their physician immediately.

Urinary Retention

Patients should be informed that POTIGA can cause urinary
retention (including urinary hesitation and dysuria). If patients experience
any symptoms of urinary retention, inability to urinate, and/or pain with
urination, they should be instructed to seek immediate medical assistance [see WARNINGS
AND PRECAUTIONS]. For patients who cannot reliably report symptoms of
urinary retention (for example, patients with cognitive impairment), urologic consultation
may be helpful.

Skin Discoloration

Inform patients that POTIGA can cause discoloration of
nails, lips, skin, palate, and parts of the eye and that it is not known if the
discoloration is reversible upon drug discontinuation [see WARNINGS AND
PRECAUTIONS]. Most skin discoloration has been reported after at least 2 years
of treatment with POTIGA, but may happen earlier. Inform patients that the
possibility of more extensive systemic involvement has not been excluded.
Instruct patients to notify their physician if they develop skin discoloration.

Psychiatric Symptoms

Patients should be informed that POTIGA can cause
psychiatric symptoms such as confusional state, disorientation, hallucinations,
and other symptoms of psychosis. Patients and their caregivers should be
instructed to notify their physicians if they experience psychotic symptoms [see
WARNINGS AND PRECAUTIONS].

Central Nervous System Effects

Patients should be informed that POTIGA may cause
dizziness, somnolence, memory impairment, abnormal coordination/balance,
disturbance in attention, and ophthalmological effects such as diplopia or
blurred vision. Patients taking POTIGA should be advised not to drive, operate
complex machinery, or engage in other hazardous activities until they have become
accustomed to any such effects associated with POTIGA [see WARNINGS AND
PRECAUTIONS].

Suicidal Thinking and Behavior

Patients, their caregivers, and families should be informed
that AEDs, including POTIGA, may increase the risk of suicidal thoughts and
behavior and should be advised of the need to be alert for the emergence or
worsening of symptoms of depression, any unusual changes in mood or behavior,
or the emergence of suicidal thoughts, behavior, or thoughts about selfharm. Behaviors
of concern should be reported immediately to healthcare providers [see WARNINGS
AND PRECAUTIONS].

Pregnancy

Patients should be advised to notify their physicians if
they become pregnant or intend to become pregnant during therapy. Patients
should be advised to notify their physicians if they intend to breastfeed or
are breastfeeding an infant.

Patients should be encouraged to enroll in the NAAED
Pregnancy Registry if they become pregnant. This registry collects information
about the safety of AEDs during pregnancy. To enroll, patients can call the
toll-free number 1-888-233-2334 [see Use In Specific Populations].

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

In a one-year neonatal mouse study of ezogabine (2 single-dose
oral administrations of up to 96 mg/kg on postnatal days 8 and 15), a
dose-related increase in the frequency of lung neoplasms (bronchioalveolar
carcinoma and/or adenoma) was observed in treated males. No evidence of
carcinogenicity was observed in rats following oral administration of ezogabine
(oral gavage doses of up to 50 mg/kg/day) for 2 years. Plasma exposure (AUC) to
ezogabine at the highest doses tested was less than that in humans at the
maximum recommended human dose (MRHD) of 1,200 mg per day.

Mutagenesis

Highly purified ezogabine was negative in the in vitro Ames
assay, the in vitro Chinese hamster ovary (CHO) Hprt gene mutation
assay, and the in vivo mouse micronucleus assay. Ezogabine was positive in the in
vitro chromosomal aberration assay in human lymphocytes. The major circulating
metabolite of ezogabine, NAMR, was negative in the in vitro Ames assay, but
positive in the in vitro chromosomal aberration assay in CHO cells.

Impairment of Fertility

Ezogabine had no effect on fertility, general
reproductive performance, or early embryonic development when administered to
male and female rats at doses of up to 46.4 mg/kg/day (associated with a plasma
ezogabine exposure [AUC] less than that in humans at the MRHD) prior to and
during mating, and continuing in females through gestation day 7.

Use In Specific Populations

Pregnancy

Pregnancy Category C

There are no adequate and well-controlled studies in
pregnant women. POTIGA should be used during pregnancy only if the potential
benefit justifies the potential risk to the fetus.

In animal studies, doses associated with maternal plasma
exposures (AUC) to ezogabine and its major circulating metabolite, NAMR,
similar to or below those expected in humans at the maximum recommended human
dose (MRHD) of 1,200 mg per day produced developmental toxicity when
administered to pregnant rats and rabbits. The maximum doses evaluated were limited
by maternal toxicity (acute neurotoxicity).

Treatment of pregnant rats with ezogabine (oral doses of
up to 46 mg/kg/day) throughout organogenesis increased the incidences of fetal
skeletal variations. The no-effect dose for embryo-fetal toxicity in rats (21
mg/kg/day) was associated with maternal plasma exposures (AUC) to ezogabine and
NAMR less than those in humans at the MRHD. Treatment of pregnant rabbits with
ezogabine (oral doses of up to 60 mg/kg/day) throughout organogenesis resulted
in decreased fetal body weights and increased incidences of fetal skeletal
variations. The no-effect dose for embryo-fetal toxicity in rabbits (12
mg/kg/day) was associated with maternal plasma exposures to ezogabine and NAMR
less than those in humans at the MRHD.

Administration of ezogabine (oral doses of up to 61.9
mg/kg/day) to rats throughout pregnancy and lactation resulted in increased
pre- and postnatal mortality, decreased body weight gain, and delayed reflex
development in the offspring. The no-effect dose for pre- and postnatal
developmental effects in rats (17.8 mg/kg/day) was associated with maternal
plasma exposures to ezogabine and NAMR less than those in humans at the MRHD.

Pregnancy Registry

To provide information regarding the effects of in utero exposure
to POTIGA, physicians are advised to recommend that pregnant patients taking
POTIGA enroll in the North American Antiepileptic Drug (NAAED) Pregnancy
Registry. This can be done by calling the toll-free number 1-888-233-2334, and
must be done by patients themselves. Information on the registry can also be
found at the website www.aedpregnancyregistry.org.

Labor and Delivery

The effects of POTIGA on labor and delivery in humans are
unknown.

Nursing Mothers

It is not known whether ezogabine is excreted in human
milk. However, ezogabine and/or its metabolites are present in the milk of
lactating rats. Because of the potential for serious adverse reactions in
nursing infants from POTIGA, a decision should be made whether to discontinue
nursing or to discontinue the drug, taking into account the importance of the
drug to the mother.

Pediatric Use

The safety and effectiveness of POTIGA in patients under
18 years of age have not been established.

In juvenile animal studies, increased sensitivity to
acute neurotoxicity and urinary bladder toxicity was observed in young rats
compared to adults. In studies in which rats were dosed starting on postnatal
day 7, ezogabine-related mortality, clinical signs of neurotoxicity, and renal and
urinary tract toxicities were observed at doses ≥ 2 mg/kg/day. The
no-effect level was associated with plasma ezogabine exposures (AUC) less than
those expected in human adults at the MRHD of 1,200 mg per day. In studies in
which dosing began on postnatal day 28, acute central nervous system effects,
but no apparent renal or urinary tract effects, were observed at doses of up to
30 mg/kg/day. These doses were associated with plasma ezogabine exposures less than
those achieved clinically at the MRHD.

Geriatric Use

There were insufficient numbers of elderly patients
enrolled in partial-onset seizure controlled trials (n = 8 patients on
ezogabine) to determine the safety and efficacy of POTIGA in this population.
Dosage adjustment is recommended in patients aged 65 years and older [see DOSAGE
AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

POTIGA may cause urinary retention. Elderly men with
symptomatic BPH may be at increased risk for urinary retention.

OVERDOSE

Signs, Symptoms, and Laboratory Findings

There is limited experience of overdose with POTIGA.
Total daily doses of POTIGA over 2,500 mg were reported during clinical trials.
In addition to adverse reactions seen at therapeutic doses, symptoms reported
with POTIGA overdose included agitation, aggressive behavior, and irritability.
There were no reported sequelae.

In an abuse potential study, cardiac arrhythmia (asystole
or ventricular tachycardia) occurred in 2 volunteers within 3 hours of
receiving a single 900-mg dose of POTIGA. The arrhythmias spontaneously
resolved and both volunteers recovered without sequelae.

Management of Overdose

There is no specific antidote for overdose with POTIGA.
In the event of overdose, standard medical practice for the management of any
overdose should be used. An adequate airway, oxygenation, and ventilation
should be ensured; monitoring of cardiac rhythm and vital sign measurement is
recommended. A certified poison control center should be contacted for updated
information on the management of overdose with POTIGA.

CONTRAINDICATIONS

CLINICAL PHARMACOLOGY

Mechanism of Action

The mechanism by which ezogabine exerts its therapeutic
effects has not been fully elucidated. In vitro studies indicate that ezogabine
enhances transmembrane potassium currents mediated by the KCNQ (Kv7.2 to 7.5)
family of ion channels. By activating KCNQ channels, ezogabine is thought to
stabilize the resting membrane potential and reduce brain excitability. In vitro
studies suggest that ezogabine may also exert therapeutic effects through
augmentation of GABA-mediated currents.

Pharmacodynamics

The QTc prolongation risk of POTIGA was evaluated in
healthy subjects. In a randomized, double-blind, active- and placebo-controlled
parallel-group study, 120 healthy subjects (40 in each group) were administered
POTIGA titrated up to the final dose of 400 mg 3 times daily, placebo, and
placebo and moxifloxacin (on day 22). After 22 days of dosing, the maximum mean
(upper 1-sided, 95% CI) increase of baseline- and placebo-adjusted QTc interval
based on Fridericia correction method (QTcF) was 7.7 msec (11.9 msec) and was
observed at 3 hours after dosing in subjects who achieved 1,200 mg per day. No
effects on heart rate, PR, or QRS intervals were noted.

Pharmacokinetics

The pharmacokinetic profile is approximately linear in
daily doses between 600 mg and 1,200 mg in patients with epilepsy, with no
unexpected accumulation following repeated administration. The pharmacokinetics
of ezogabine are similar in healthy volunteers and patients with epilepsy.

Absorption

After both single and multiple oral doses, ezogabine is
rapidly absorbed with median time to maximum plasma concentration (Tmax) values
generally between 0.5 and 2 hours. Absolute oral bioavailability of ezogabine
relative to an intravenous dose of ezogabine is approximately 60%. High-fat
food does not affect the extent to which ezogabine is absorbed based on plasma
AUC values, but it increases peak concentration (Cmax) by approximately 38% and
delays Tmax by 0.75 hour.

POTIGA can be taken with or without food.

Distribution

Data from in vitro studies indicate that ezogabine and
NAMR are approximately 80% and 45% bound to plasma protein, respectively.
Clinically significant interactions with other drugs through displacement from
proteins are not anticipated. The steadystate volume of distribution of
ezogabine is 2 to 3 L/kg following intravenous dosing, suggesting that
ezogabine is well distributed in the body.

Metabolism

Ezogabine is extensively metabolized primarily via
glucuronidation and acetylation in humans. A substantial fraction of the
ezogabine dose is converted to inactive Nglucuronides, the predominant
circulating metabolites in humans. Ezogabine is also metabolized to NAMR that
is also subsequently glucuronidated. NAMR has antiepileptic activity, but it is
less potent than ezogabine in animal seizure models. Additional minor
metabolites of ezogabine are an N-glucoside of ezogabine and a cyclized
metabolite believed to be formed from NAMR. In vitro studies using human
biomaterials showed that the N-acetylation of ezogabine was primarily carried
out by NAT2, while glucuronidation was primarily carried out by UGT1A4, with
contributions by UGT1A1, UGT1A3, and UGT1A9.

In vitro studies showed no evidence of oxidative
metabolism of ezogabine or NAMR by cytochrome P450 enzymes. Coadministration of
ezogabine with medications that are inhibitors or inducers of cytochrome P450
enzymes is therefore unlikely to affect the pharmacokinetics of ezogabine or
NAMR.

Elimination

Results of a mass balance study suggest that renal
excretion is the major route of elimination for ezogabine and NAMR. About 85%
of the dose was recovered in the urine, with the unchanged parent drug and NAMR
accounting for 36% and 18% of the administered dose, respectively, and the
total N-glucuronides of ezogabine and NAMR accounting for 24% of the
administered dose. Approximately 14% of the radioactivity was recovered in the
feces, with unchanged ezogabine accounting for 3% of the total dose. Average total
recovery in both urine and feces within 240 hours after dosing is approximately
98%.

Ezogabine and its N-acetyl metabolite have similar
elimination half-lives (t/2) of 7 to 11 hours. The clearance of ezogabine
following intravenous dosing was approximately 0.4 to 0.6 L/hr/kg. Ezogabine is
actively secreted into the urine.

Specific Populations

Race: No study has been conducted to investigate
the impact of race on pharmacokinetics of ezogabine. A population
pharmacokinetic analysis comparing Caucasians and non-Caucasians (predominately
African American and Hispanic patients) showed no significant pharmacokinetic
difference. No adjustment of the ezogabine dose for race is recommended.

Gender: The impact of gender on the pharmacokinetics
of ezogabine was examined following a single dose of POTIGA to healthy young
(aged 21 to 40 years) and elderly (aged 66 to 82 years) subjects. The AUC
values were approximately 20% higher in young females compared to young males
and approximately 30% higher in elderly females compared to elderly males. The
Cmax values were approximately 50% higher in young females compared to young males
and approximately 100% higher in elderly females compared to elderly males.
There was no gender difference in weight-normalized clearance. Overall, no
adjustment of the dosage of POTIGA is recommended based on gender.

Pediatric Patients: The pharmacokinetics of
ezogabine in pediatric patients have not been investigated.

Geriatric: The impact of age on the pharmacokinetics
of ezogabine was examined following a single dose of ezogabine to healthy young
(aged 21 to 40 years) and elderly (aged 66 to 82 years) subjects. Systemic
exposure (AUC) of ezogabine was approximately 40% to 50% higher and terminal
half-life was prolonged by approximately 30% in the elderly compared to the younger
subjects. The peak concentration (Cmax) was similar to that observed in younger
subjects. A dosage reduction in the elderly is recommended [see DOSAGE AND
ADMINISTRATION, Use In Specific Populations].

Renal Impairment: The pharmacokinetics of
ezogabine were studied following a single 100-mg dose of POTIGA in subjects
with normal (CrCL > 80 ml/min), mild (CrCL ≥ 50 to < 80 mL/min),
moderate (CrCL ≥ 30 to < 50 mL/min), or severe renal impairment (CrCL
< 30 mL/min) (n = 6 in each cohort) and in subjects with ESRD requiring
hemodialysis (n = 6). The ezogabine AUC was increased by approximately 30% in
patients with mild renal impairment and doubled in patients with moderate
impairment to ESRD (CrCL < 50 mL/min) relative to healthy subjects. Similar
increases in NAMR exposure were observed in the various degrees of renal impairment.
The effect of hemodialysis on ezogabine clearance has not been established.
Dosage reduction is recommended for patients with creatinine clearance < 50
mL/min and for patients with ESRD receiving dialysis [see DOSAGE AND
ADMINISTRATION, Use In Specific Populations].

Hepatic Impairment: The pharmacokinetics of
ezogabine were studied following a single 100-mg dose of POTIGA in subjects
with normal, mild (Child-Pugh score 5 to 6), moderate (Child-Pugh score 7 to
9), or severe hepatic (Child-Pugh score > 9) impairment (n = 6 in each
cohort). Relative to healthy subjects, ezogabine AUC was not affected by mild
hepatic impairment, but was increased by approximately 50% in subjects with
moderate hepatic impairment and doubled in subjects with severe hepatic
impairment. There was an increase of approximately 30% in exposure to NAMR in
patients with moderate to severe impairment. Dosage reduction is recommended
for patients with moderate and severe hepatic impairment [see DOSAGE AND
ADMINISTRATION, Use In Specific Populations].

Drug Interactions

In vitro studies using human liver microsomes
indicated that ezogabine does not inhibit enzyme activity for CYP1A2, CYP2A6,
CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1, and CYP3A4/5. Inhibition of CYP2B6 by
ezogabine has not been evaluated. In addition, in vitro studies in human
primary hepatocytes showed that ezogabine and NAMR did not induce CYP1A2 or
CYP3A4/5 activity. Therefore, ezogabine is unlikely to affect the
pharmacokinetics of substrates of the major cytochrome P450 isoenzymes through
inhibition or induction mechanisms.

Ezogabine is neither a substrate nor an inhibitor of
P-glycoprotein, an efflux transporter. NAMR is a P-glycoprotein inhibitor. Data
from an in vitro study showed that NAMR inhibited P-glycoprotein-mediated
transport of digoxin in a concentration-dependent manner, indicating that NAMR
may inhibit renal clearance of digoxin. Administration of POTIGA at therapeutic
doses may increase digoxin serum concentrations [see DRUG INTERACTIONS].

Interactions with Antiepileptic Drugs: The
interactions between POTIGA and concomitant AEDs are summarized in Table 6.

a Based on results of a Phase 2 study.b Inducer for uridine 5'-diphosphate (UDP)-glucuronyltransferases
(UGTs).c A decrease in dose of POTIGA should be considered when
carbamazepine or phenytoin is discontinued.d Zonisamide, valproic acid, clonazepam, gabapentin, levetiracetam,
oxcarbazepine, phenobarbital, pregabalin, topiramate, clobazam, and
lamotrigine, based on a population pharmacokinetic analysis using pooled data
from Phase 3 clinical trials.

Oral Contraceptives: In one study examining the
potential interaction between ezogabine (150 mg 3 times daily for 3 days) and
the combination oral contraceptive norgestrel/ethinyl estradiol (0.3 mg/0.03
mg) tablets in 20 healthy females, no significant alteration in the
pharmacokinetics of either drug was observed.

In a second study examining the potential interaction of
repeated ezogabine dosing (250 mg 3 times daily for 14 days) and the
combination oral contraceptive norethindrone/ethinyl estradiol (1 mg/0.035 mg)
tablets in 25 healthy females, no significant alteration in the pharmacokinetics
of either drug was observed.

Alcohol: In a healthy volunteer study, the
coadministration of ethanol 1g/kg (5 standard alcohol drinks) over 20 minutes
and ezogabine (200 mg) resulted in an increase in the ezogabine Cmax and AUC by
23% and 37%, respectively [see DRUG INTERACTIONS].

Clinical Studies

The efficacy of POTIGA as adjunctive therapy in
partial-onset seizures was established in 3 multicenter, randomized,
double-blind, placebo-controlled studies in 1,239 adult patients. The primary
endpoint consisted of the percent change in seizure frequency from baseline in
the double-blind treatment phase.

Patients enrolled in the studies had partial onset
seizures with or without secondary generalization and were not adequately
controlled with 1 to 3 concomitant AEDs, with or without concomitant vagus
nerve stimulation. More than 75% of patients were taking 2 or more concomitant
AEDs. During an 8-week baseline period, patients experienced at least 4 partial
onset seizures per 28 days on average with no seizure-free period exceeding 3
to 4 weeks. Patients had a mean duration of epilepsy of 22 years. Across the 3
studies, the median baseline seizure frequency ranged from 8 to 12 seizures per
month. The criteria for statistical significance was P < 0.05.

Patients were randomized to the total daily maintenance
dosages of 600 mg per day, 900 mg per day, or 1,200 mg per day, each
administered in 3 equally divided doses. During the titration phase of all 3
studies, treatment was initiated at 300 mg per day (100 mg 3 times per day) and
increased in weekly increments of 150 mg per day to the target maintenance
dosage.

Figure 1 shows the median percent reduction in 28-day
seizure frequency (baseline to double-blind phase) as compared with placebo
across all 3 studies. A statistically significant effect was observed with
POTIGA at doses of 600 mg per day (Study 1), at 900 mg per day (Studies 1 and
3), and at 1,200 mg per day (Studies 2 and 3).

Figure 1: Median Percent Reduction From Baseline in
Seizure Frequency per 28 Days by Dose

Figure 2 shows changes from baseline in the 28-day total
partial seizure frequency by category for patients treated with POTIGA and
placebo in an integrated analysis across the 3 clinical trials. Patients in
whom the seizure frequency increased are shown at left as “worse.” Patients in
whom the seizure frequency decreased are shown in five categories.

Figure 2: Proportion of Patients by Category of
Seizure Response for POTIGA and Placebo Across All Three Double-blind Trials

PATIENT INFORMATION

POTIGA™
(po-TEE-ga)
(ezogabine) Tablets

Read this Medication Guide before you start taking POTIGA
and each time you get a refill. There may be new information. This Medication
Guide does not take the place of talking to your healthcare provider about your
medical condition or treatment. If you have questions about POTIGA, ask your
healthcare provider or pharmacist.

What is the most important information I should know
about POTIGA?

Do not stop POTIGA without first talking to a healthcare
provider. Stopping POTIGA suddenly can cause serious problems. Stopping POTIGA
suddenly can cause you to have more seizures more often.

1. POTIGA can cause changes to your retina, which is
located in the back of your eye and is needed for vision. These types of
changes can cause vision loss.

If a decrease in your vision happens, it is not known if
it will get better.

You and your healthcare provider should decide if the
benefit of taking POTIGA is more important than the possible risk of vision
loss.

You should have a complete eye exam if you are currently
taking POTIGA or before starting treatment, and then every 6 months while
taking POTIGA.

Tell your healthcare provider right away if you notice
any changes in your vision.

2. POTIGA can make it hard for you to urinate (empty
your bladder) and may cause you to be unable to urinate. Call your healthcare
provider right away if you:

are unable to start urinating

have trouble emptying your bladder

have a weak urine stream

have pain with urination

3. POTIGA can cause changes in the color of your skin,
nails, lips, roof of your mouth, and whites of your eyes or insides of your
eyelids.

The changes in color may be blue, grey-blue, or brown.

Most changes in color have happened in people who have
taken POTIGA for at least 2 years, but may happen earlier.

It is not known if the changes in color go away after
stopping POTIGA.

Tell your healthcare provider if you notice any changes
in color to your body.

Call your healthcare provider between visits as needed,
especially if you are worried about symptoms.

What is POTIGA?

POTIGA is a prescription medicine that is used with other
medicines to treat partialonset seizures in adults with epilepsy when several
other medicines have not worked well. POTIGA is used when the benefit of taking
it is more important than the possible risk of vision loss.

POTIGA is a controlled substance (CV) because it can be
abused or lead to drug dependence. Keep your POTIGA in a safe place to protect
it from theft. Never give your POTIGA to anyone else because it may harm them.
Selling or giving away this medicine is against the law.

It is not known if POTIGA is safe and effective in
children under 18 years of age.

have or have had depression, mood problems, or suicidal
thoughts or behavior

have heart problems, including a condition called long QT
Syndrome, or have low potassium or magnesium in your blood

have liver problems

have kidney problems

drink alcohol

have any other medical conditions

are pregnant or plan to become pregnant. It is not known
if POTIGA will harm your unborn baby.

If you become pregnant while taking POTIGA, talk to your
healthcare provider about registering with the North American Antiepileptic
Drug
Pregnancy Registry. The purpose of this registry is to collect information about
the safety of medicines used to treat seizures during pregnancy. You can enroll
in this registry by calling 1-888-233-2334.

are breastfeeding or plan to breastfeed. It is not known
if POTIGA passes into your breast milk. Talk to your healthcare provider about
the best way to feed your baby if you take POTIGA. You and your healthcare
provider should decide if you will take POTIGA or breastfeed. You should not do
both.

Tell your healthcare provider about all the medicines
you take, including prescription and over-the-counter medicines, vitamins,
and herbal supplements. Taking POTIGA with certain other medicines can affect
each other, causing side effects.

If you take too much POTIGA, call your local Poison
Control Center or go to the nearest hospital emergency room right away.

What should I avoid while taking POTIGA?

Do not drive, operate machinery, or do other dangerous
activities until you know how POTIGA affects you. POTIGA can cause dizziness,
sleepiness, double-vision, and blurred vision.

What are the possible side effects of POTIGA?

POTIGA may cause serious side effects, including:

See “What is the most important information I should
know about POTIGA?”

Dizziness and sleepiness. These symptoms can
increase when your dose of POTIGA is increased. See “What should I avoid
while taking POTIGA?”

Changes in your heart rhythm and the electrical
activity of your heart. Your healthcare provider should monitor your heart
during treatment if you have a certain type of heart disease or take certain
medications.

Drinking alcohol during treatment with POTIGA may
increase the side effects that you get with POTIGA.

problems with balance and muscle coordination, including
trouble with walking and moving

blurred or double vision

trouble concentrating

memory problems

weakness

Tell your healthcare provider about any side effect that
bothers you or that does not go away.

These are not all the possible side effects of POTIGA.
Ask your healthcare provider or pharmacist for more information.

Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.

How should I store POTIGA?

Store POTIGA at room temperature between 68°F and 77°F
(20°C and 25°C).

Keep POTIGA and all medicines out of the reach of
children.

General information about the safe and effective use
of POTIGA.

Medicines are sometimes prescribed for purposes other
than those listed in a Medication Guide. Do not use POTIGA for a condition for
which it was not prescribed. Do not give POTIGA to other people, even if they
have the same symptoms you have. It may harm them.

This Medication Guide summarizes the most important
information about POTIGA. If you would like more information, talk with your
healthcare provider. You can ask your healthcare provider or pharmacist for
information about POTIGA that is written for healthcare professionals.

For more information, go to www.potiga.com or call
1-877-3POTIGA (1-877-3768442).